WO1993023420A1 - NEW 7β-SUBSTITUTED-4-AZA-5α-ANDROSTAN-3-ONES AS 5α-REDUCTASE INHIBITORS - Google Patents
NEW 7β-SUBSTITUTED-4-AZA-5α-ANDROSTAN-3-ONES AS 5α-REDUCTASE INHIBITORS Download PDFInfo
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- WO1993023420A1 WO1993023420A1 PCT/US1993/004643 US9304643W WO9323420A1 WO 1993023420 A1 WO1993023420 A1 WO 1993023420A1 US 9304643 W US9304643 W US 9304643W WO 9323420 A1 WO9323420 A1 WO 9323420A1
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- 0 CN(*)CC(**)=* Chemical compound CN(*)CC(**)=* 0.000 description 14
- UJSGXLHOEMUFIG-ZJKCBAOMSA-N CC(CN)C(CC1)C(C)(CC2)C1C(CC1)C2C(C)(CC2)[C@@H]1NC2=O Chemical compound CC(CN)C(CC1)C(C)(CC2)C1C(CC1)C2C(C)(CC2)[C@@H]1NC2=O UJSGXLHOEMUFIG-ZJKCBAOMSA-N 0.000 description 1
- HNRHMOOIPRDAGD-XTFRJMTMSA-N CC[C@H](CCC1)[C@@H]2C1CC[C@H]1NCOC21 Chemical compound CC[C@H](CCC1)[C@@H]2C1CC[C@H]1NCOC21 HNRHMOOIPRDAGD-XTFRJMTMSA-N 0.000 description 1
- WRFAKIXSBJDLRL-SDFDYJRSSA-N C[C@@H]([C@@H](CC1)[C@@](C)(CC2)C1C(CC1)C2[C@@](C)(CC2)[C@@H]1N(C)C2=O)C(Sc1ccccn1)=O Chemical compound C[C@@H]([C@@H](CC1)[C@@](C)(CC2)C1C(CC1)C2[C@@](C)(CC2)[C@@H]1N(C)C2=O)C(Sc1ccccn1)=O WRFAKIXSBJDLRL-SDFDYJRSSA-N 0.000 description 1
- NUKYPUAOHBNCPY-UHFFFAOYSA-N Nc1ccncc1 Chemical compound Nc1ccncc1 NUKYPUAOHBNCPY-UHFFFAOYSA-N 0.000 description 1
- JUJWROOIHBZHMG-UHFFFAOYSA-N c1ccncc1 Chemical compound c1ccncc1 JUJWROOIHBZHMG-UHFFFAOYSA-N 0.000 description 1
Classifications
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07J—STEROIDS
- C07J51/00—Normal steroids with unmodified cyclopenta(a)hydrophenanthrene skeleton not provided for in groups C07J1/00 - C07J43/00
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P13/00—Drugs for disorders of the urinary system
- A61P13/02—Drugs for disorders of the urinary system of urine or of the urinary tract, e.g. urine acidifiers
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P15/00—Drugs for genital or sexual disorders; Contraceptives
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P17/00—Drugs for dermatological disorders
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P43/00—Drugs for specific purposes, not provided for in groups A61P1/00-A61P41/00
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C59/00—Compounds having carboxyl groups bound to acyclic carbon atoms and containing any of the groups OH, O—metal, —CHO, keto, ether, groups, groups, or groups
- C07C59/40—Unsaturated compounds
- C07C59/76—Unsaturated compounds containing keto groups
- C07C59/80—Unsaturated compounds containing keto groups containing rings other than six-membered aromatic rings
- C07C59/82—Unsaturated compounds containing keto groups containing rings other than six-membered aromatic rings the keto group being part of a ring
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C59/00—Compounds having carboxyl groups bound to acyclic carbon atoms and containing any of the groups OH, O—metal, —CHO, keto, ether, groups, groups, or groups
- C07C59/40—Unsaturated compounds
- C07C59/76—Unsaturated compounds containing keto groups
- C07C59/90—Unsaturated compounds containing keto groups containing singly bound oxygen-containing groups
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07J—STEROIDS
- C07J73/00—Steroids in which the cyclopenta[a]hydrophenanthrene skeleton has been modified by substitution of one or two carbon atoms by hetero atoms
- C07J73/001—Steroids in which the cyclopenta[a]hydrophenanthrene skeleton has been modified by substitution of one or two carbon atoms by hetero atoms by one hetero atom
- C07J73/005—Steroids in which the cyclopenta[a]hydrophenanthrene skeleton has been modified by substitution of one or two carbon atoms by hetero atoms by one hetero atom by nitrogen as hetero atom
Definitions
- the present invention is directed to new 7 ⁇ -substituted-4-aza-5 ⁇ -androstan-3-ones and related compounds and the use of such compounds as 5 ⁇ -reductase inhibitors.
- BPH benign prostatic hyperplasia
- DHT dihydrotesterone
- PROSCAR® farnesoyl
- the present invention discloses novel 7 ⁇ -substituted-4-aza-5 ⁇ -androstan-3-one compounds which are useful for inhibiting the 5 ⁇ -reductase isozymes 1 and/or 2 and are particularly effective in selectively inhibiting the 5 ⁇ -reductase 1 associated with the scalp and indually inhibiting both isozymes 1 and 2 in the treatment of benign prostatic hyperplasia, acne, female hirsutism, male pattern baldness, androgenic alopecia, prostatitis, and the prevention and treatment of prostatic carcinoma.
- R is selected from hydrogen, methyl or ethyl; the dashed lines-a, b, e indicate double bonds which can be present, providing that if double bond b is present, then the 5 ⁇ hydrogen, Ha, is not present;
- Z can be:
- COOC 1 -C 4 alkyl esters OCONR 1 R 2 , where R 1 and R 2 are independently H C 1 -C 4 alkyl, phenyl, benzyl, and where R 1 and R 2 together with the nitrogen can form a
- R 1 is H, C 1 -C 4 alkyl
- A can be:
- R 3 is independently hydrogen, methyl or ethyl
- R 2 is a hydrocarbon radical, selected from substituted or unsubstituted straight or branched chain alkyl, cycloalkyl, or aralkyl of from 1-12 carbons or monocyclic aryl optionally containing 1 or more lower alkyl substituents of from 1-2 carbon atoms and/or 1 or more halogen substituents, with the proviso that Z is not beta-methyl where R 2 is C 1 -C 8 alkyl;
- a monovalent aliphatic radical selected from straight or branched chain alkyl, or cycloalkyl, of from 1- 12 carbons, which can be substituted by one or more of C 1 -C 2 alkyl or halo, excluding C 1 -C 4 alkyl when Z is beta-methyl;
- a polycyclic aromatic radical which can be substituted with one or more of: -OH, organosilyl protected -OH, -OC 1 -C 4 alkyl, C 1 -C 4 alkyl, halo or nitro;
- heterocyclic selected from 2-, 3-, or 4- pyridyl, 2-pyrrolyI, 2-furyl or thiophenyl;
- A is -XR 4 , or- (CHR 1 ) n -XR 4 ;
- n 1-10;
- X is -O- or -S(O) p -
- p is zero, 1 or 2;
- R 4 can be the same or different when n is greater than 1 and is -H, aryl, or -C 1-3 alkyl unsubstituted or substituted with C 6 - C 10 aryl;
- R is -H, methyl or ethyl
- R 4 is 1) hydrogen or -C 1-20 alkyl, unsubstituted or substituted with one or more of:
- heterocyclic defined below, unsubstituted or substituted with one or more of R 7 or R 9 , f) -COOR 6 , wherein R 6 is
- aryl unsubstituted or substituted with one or more of aryl, R 7 or R 9 ,
- R 9 ; R 7 is l) -OH
- R 9 is 1) -C 1-8 alkyl, unsubstituted or substituted with one or more of aryl or R 7 ,
- A is (CHR 1 ) n -X-C-R 4 ;
- R 1 can be the same or different when n is greater than 1 and is -H, aryl, or -C 1-3 alkyl unsubstituted or substituted with aryl;
- R is -H, methyl or ethyl
- n zero through 10;
- X is -O- or -S-;
- R 4 is 1) hydrogen or -C 1 - 20 alkyl, unsubstituted or substituted with one or more of:
- aryl unsubstituted or substituted with one or more of aryl, R 7 or R 9 ,
- cycloalkyl such as cyclohexyl, norbornyl, or adamantyl, unsubstituted or substituted with one or more of R 7 or R 9 , or
- R 7 is 1) -OH
- R 9 is 1) -C 1-8 alkyl, unsubstituted or substituted with one or more of aryl or R 7 ,
- R 4 is not substituted with an unsubstituted phenyl ring
- R 4 when n is 1-12, R 1 is -H at each occurrence, and X is -O-, R 4 is not unsubstituted C 5- 10 cycloalkyl, unsubstituted phenyl, amino, -C 1-8 alkyl substituted amino, or -C 1-8 alkoxy; and when n is zero, R 4 is not -CH 3 ; and
- R 2 is:
- R 3 is:
- R 4 is:
- R 5 can be the same or different when X is greater than 1 and is:
- W is:
- O x is an integer from 1-25;
- A is:
- R 6 and R 3 can not be independently selected from H, C 1-8 alkyl, C 3-6 cycloalkyl, phenyl and R 6 and R 3 cannot be taken together with the adjacent N to form a 5-6 membered ring comprising up to one other heteroatom selected from O or N, or
- R 2 is:
- R 3 is:
- R 4 is:
- R 5 can be the same or different when X is greater than 1 and is:
- R 6 is present when X equals N and is independently
- A is (a)
- D is R 1 or OR 1 ,
- R 1 is: C 1 -C 10 alkyl
- Alk is C 1 -C 4 straight or branched chain alkyl or alkenyl; dashed
- Knes e and f each can independently represent a double bond when present, with the proviso that double bonds formed by e and f are not both present concurrently;
- R 2 is (a) C 6 -C 10 aryl, or 5-6 membered heteroaryl radical which can contain 1-4 nitrogen atoms, one oxygen or sulfur atoms or combinations thereof with 1-2 nitrogen atoms; (b) COR 1 , where R 1 is C 6 -C 10 aryl, substituted C 6 -C 10 aryl, and heteroaryl;
- R 20 is H, methyl
- n 0-10
- R 4 is selected from:
- heteroaryl substituted heteroaryl
- heteroaryl can be substituted; wherein the above aryl or heteroaryl radicals can also be fused with a benzo or another heteroraryl ring and can further be substituted with one or more
- C 1 -C 4 alkyl as used herein, is meant to include: e.g. methyl, ethyl, propyl, isopropyl, n-butyl, sec-butyl, isobutyl and t-butyl.
- C 2 -C 4 alkenyl as used herein is meant to include: vinyl, allyl, 1-propen-1-yl, 1-propen-2-yl, 1-buten-1-yl, 1-buten-2-yl, and the like.
- C 3 -C 6 cycloalkyl as used herein is meant to include: cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl.
- halo as used herein is meant to include: fluoro, chloro, bromo, iodo.
- OC 1 -C 4 alkyl as used herein is meant to include: methoxy, ethoxy, propoxy, isopropoxy, n-butoxy, isobutoxy, sec-butoxy, t-butoxy.
- OC 3 -C 6 cycloalkyl as used herein is meant to include: cyclopropyloxy, cyclobutyloxy, cyclopentyloxy, cyclohexyloxy.
- beta substituent is e.g. methyl, ethyl, propyl, allyl, carboxymethyl, hydroxy, methoxy, ethoxy, cyclopropyloxy, cyclopentyloxy, acetoxy, fluoro, chloro, bromo, trifluoromethyl, trichloromethyl, fluoromethyl,
- R 1 , R 2 and the N can form a heterocyclic ring include: N-morpholinyl, N-(4-methyl)piperazinyl, N-piperidinyl, and the like.
- Z is the spiro substituent:
- the first group of preferred compounds of this invention can be made by procedures outlined in the following Flowsheets:
- the compounds of the instant invention comprising Z as a 7 ⁇ alkyl group, e.g. methyl, ethyl, isopropyl, where A is defined above, can be prepared by the procedure outlined in The General Flowsheet.
- the 3-acetoxy-androst-5-en- 17-A I is oxidized to the corresponding 5-en-7-one II by treatment with hydrogen t-butyl peroxide and chromium hexacarbonyl in e.g. acetonitrile, at reflux.
- the C 1 -C 4 alkyl group, designated Alk, e.g. methyl can be introduced at this point by a Grignard reaction using e.g., alkyl magnesium chloride in e.g., anhydrous THF at 0-10°C to produce the 7-alkyl-7-hydroxy adduct ffl. This is then oxidized with e.g.
- seco-acid VII permanganate, sodium periodate in t-butyl alcohol at 80°C to produce the corresponding seco-acid VII.
- the seco-acid VII can be similarly treated with ammonia to produce the corresponding N-H compound, X, which can then be analogously treated with PtO 2 to produce the corresponding 5 ⁇ -4N-H compound XI.
- A is hydroxy or derivatived hydroxy and Z is an 7 ⁇ alkyl group, e.g. methyl, ethyl, propyl, isopropyl, allyl, can be prepared by the procedure outlined in Flowsheets A and B.
- the 3-acetoxy-androst-5-en-17-one 1 is reacted with sodium borohydride in a suitable solvent, e.g. ethanol, at -10°C to stereospecifically reduce the 17-ketone to the 17 ⁇ -ol 2.
- a suitable solvent e.g. ethanol
- the 17-hydroxy group is protected with the TBS group (t-butyldimethyl-silyl) by reacting TBS chloride with 2 in a suitable solvent, e.g. DMF in the presence of the proton acceptor, e.g.
- this compound is oxidized in the seven position to the corresponding 5-en-7-one 4 by treatment of 3. with hydrogen t-butyl peroxide and chromium hexacarbonyl in e.g. acetonitrile, at reflux.
- the alkyl group e.g. methyl
- This Grignard product is then oxidized with aluminum isopropoxide and cyclohexanone (Oppenauer oxidation conditions) in refluxing toluene solvent to produce the 7-methyI-4,6-dien-3-one 6.
- This in turn is reduced via a metal-ammonia reduction using lithium in liquid ammonia, THF and toluene at -78 °C to selectively yield the 7-beta-methyl-5-en-3-one 7.
- the 5-double bond is isomerized to the 4-ene by use of DBU (1,8-diazabicyclo[5.4.0]undec-7-ene) in refluxing
- THF tetrahydrofuran
- the A Ring is next cleaved by treatment with potassium permanganate, sodium periodate in t-butyl alcohol at 80°C to produce the corresponding seco-acid 9.
- the TBS protecting group is then removed e.g., by aqueous HF in acetonitrile at 0°C, to yield the 17- ⁇ alcohol 11. This in turn is selectively reduced to remove the 5-double bond to produce the 5 ⁇ -hydrogen compound 12.
- the 17 ⁇ hydroxy group can be
- 12. can be reacted with an isocyanate, e.g. t-butyl-isocyanate in a solvent and in the presence of DBU to yield the urethane ester 14.
- an isocyanate e.g. t-butyl-isocyanate in a solvent and in the presence of DBU to yield the urethane ester 14.
- the 7-carboxy substituent is formed through the corresponding 7-allyI group.
- acetate 4 is reacted with allyl Grignard reagent to form the adduct 15 which is oxidized to the dienone 16 by Oppenauer oxidation conditions.
- Flowsheet D starting with the 7-allyl-4-en-3-one 18., which is reduced by Wilkinson's catalyst to the propyl derivative 22, oxidized to the seco-acid 23, then condensed with amines, e.g. methylamine, to form the 4-methyl analog 24 and then reduced to the 5-alpha 25.
- Corresponding treatment with ammonia is shown in Flowsheet E shows the corresponding unsubstituted 4-aza 26 and 5-alpha 27 analogs.
- the 7-beta acetoxy series is prepared as illustrated in Flowsheets F and G by the oxidation of starting ester 28 to the 5-en-7-one 29 by the chromiumhexacarbonyl/t-butylhydroperoxide/-acetonitrile procedure described above. Platinum catalyzed hydrogenation of 29 yields two products, the fiilly reduced 7-H compound 31, and 7-beta hydroxy compound 32. Acylation of 32 with acetic anhydride yields the 7-beta acetoxy compound 33.
- the compound 34 is known in the art. This in can be oxidized with the chromium carbonyl reagent to yield the 5-en-7-one 35. The 5-double bond is catalytically reduced to yield the 7-one 36.
- This series can be prepared as illustrated in Flowsheet I starting with the 7-beta methyl-4-N-methyl-17-ol 12. This is oxidized to the 17-keto compound 37, by the use of
- TPAP tetrapropylammonium perruthenate
- NMO N- methylmorphiline-N-oxide
- the amine 39 can be reacted with a variety of acylating agents. Reaction with pivaloyl chloride in methylene chloride, pyridine, 4-dimethylamino pyridine (DMAP), yields 40, the "reverse finasteride"; reaction with 1-adamantane carbonyl chloride yields the 1-ADM 41; and reaction with benzyl chloride yields the benzoyl derivative 42.
- DMAP 4-dimethylamino pyridine
- Reaction of the amine 39 with different chloroformates yields the corresponding urethanes.
- Reaction of 39 with 1-adamantyl fluoroformate in DMAP, pyridine and methylene chloride yields the urethane 43; reaction with e.g. benzyl chloroformate
- acylating agents and chloroformates known in the art can be used to produce the corresponding acyl and urethane compounds.
- the present invention is particularly concerned with providing a method of treating the hyperandrogenic conditions of androgenic alopecia, acne vulgaris, seborrhea, and female hirsutism, benign prostatic hyperplasia, prostatitis, the prevention and/or treatment of prostatic carcinoma, by oral, topical, or parenteral administration, of the novel compounds of the present invention.
- Example 2 being 5.6 g (12.55 mmol) in 100 ml acetonitrile at 23 °C was added 90% t-butyl hydrogen peroxide, 3.958g (43.92 mol), and 138 mg chromium hexacarbonyl. After refluxing the mixture under nitrogen for 24 hours, the reaction mixture was poured into one liter water, solid was filtered, the residue washed with 500 ml water and the residue dissolved in 350 ml methylene chloride. The organic layer was washed with brine, dried over sodium sulfate and
- a preferred embodiment of the compound of general formula I is where A is structure IA (1) is represented by the general structural formula II:
- R 1 is hydrogen, methyl or ethyl
- R 2 is branched chain alkyl cycloalkyl, aralkyl of from 4-12 carbons, phenyl, optionally substituted by methyl, chloro or fluoro, substituted or unsubstituted 1-, 2-adamantyl, 1-, 2- adamantylmethyl, 1-, 2- or 7-norbornanyl, 1-, 2- or 7- norbornanymethyl.
- Representative compounds to which the 16-substituent may be introduced include the following:
- linear/branched alkyl including methyl, ethyl, isopropyl, n-butyl; nitro; oxo; C 7 -C 9 aralkyl, including benzyl; (CH 2 )n COOR where n is 0-2 and R is H or C 1 -C 4 linear/branched alkyl including methyl, ethyl; CH 2 OH; OH; OR where R is C 1 -C 4 linear/branched alkyl including methyl, ethyl; halo, including fluoro, bromo, iodo; COOH; COOR, where R is linear/branched C 1 -C 4 alkyl; -CONH 2 ; CH 2 NH 2 ; CH 2 NHCOR where R is C 1 -C 4 linear/branched alkyl including methyl, ethyl; phenyl; 0, m, p-substituted phenyl including p-nitro, p-amino
- compositions or esters where a basic or acidic group is present on the substituted alkyl, cycloalkyl, aralkyl, adamantyl or norbornanyl moiety.
- an acidic substituent i.e. -COOH
- ammonium, sodium, potassium, calcium salt, and the like for use as the dosage form.
- a basic group i.e. amino
- acidic salts i.e. hydrochloride, hydrobromide, acetate, pamoate, and the like
- a basic group i.e. amino
- acidic salts i.e. hydrochloride, hydrobromide, acetate, pamoate, and the like
- esters can be employed, e.g. acetate, maleate, pivaloyloxymethyl, and the like, and those esters known in the art for modifying solubility or hydrolysis characteristics for use as sustained release or prodrug formulations.
- R 2 as substituted norbomanyl moieties are (where NB is norborn-anyl):
- novel compounds of formula I of the present invention can be prepared by a method starting with the known steroid esters (III) of the formula:
- 17ß-(carbomethoxy)-4-aza-5- ⁇ -androstan-3-ones which includes the stages of optionally 1) dehydrogenating said starting material to produce the corresponding compound containing a double-bond in the 1,2-position of the A-ring, 2) converting the 17-carbomethoxy substituent into an N-substituted alkyl, cycloalkyl, aralkyl, monocylic acyl, or adamantylcarbamoyl substituent and, if desired, 3) alkylating the A-ring nitrogen to introduce a N-methyl or N-ethyl substituent into the A ring 4-position.
- the 4-aza nitrogen it is preferable that the 4-aza nitrogen be
- the alternate pathways can consist of one or more discrete chemical steps and if desired can take place before step (1) or following step (1) or step (3).
- the starting materials are formed by optionally: (1) heating a 17ß-alkoxycarbonyl-4-aza-5 ⁇ -androstan-3-ones, compound III, (prepared in the literature as described in the reference US Patent 4,377,584) with a dehydrogenating agent such as benzeneseleninic anhydride in a refluxing inert solvent, e.g.
- the corresponding N-unsubstituted-17ß(N-adamantyl-carbamoyl)-4-aza-5 ⁇ -androst-1-en-3-one XIV is readily prepared from the 17ß (alkoxycarbonyl)-4-aza-5 ⁇ -androstone-3-one IV by repeating the above series of reaction steps but omitting the alkylation Step 2 herein above, i.e. treatment of the 4-aza-5 ⁇ -androst-1-en-3-one with e.g. sodium amide followed by methyl or ethyl iodide via
- substituent X is benzotriazoloxy group.
- X is 2-pyridylthio or 1-benzotriazoloxy.
- R 2 is 1- or 2-adamantyl or norbomanyl.
- Another preferred embodiment of the compounds of our invention is the compound of above general structure I, wherein the dotted line between the A ring positions 1 and 2 is a double bond,
- R is hydrogen or methyl
- A is COQ where "Q” is branched chain alkyl, or cycloalkyl of from 4- 10 carbons .
- Another embodiment of the invention is the compounds of above Structure I where "Q" is phenyl, or phenyl substituted by substituents described above, including where
- Q is phenyl, 2-, 3-, or 4-tolyl, xylyl, 2-bromophenyl, 2- chlorophenyl, 2,6-dichlorophenyl, 2,6-dibromophenyl, aminophenyl, N-alkylaminophenyl, N-N-dialkyl- aminophenyl, 4-biphenyl, 3-biphenyl, naphthyl, anthracyl, phenanthryl, thiophenyl, methylthiophenyl, methylsulfinyl, phenyl, methylsulfophenyl,
- acetoxymethylthiophenyl 17ß-(4-hydroxyphenyl), 17ß- (3-hydroxyphenyl), 17ß-(3,4-dihydroxyphenyl), or 17ß- (3,5-dimethyl-4-hydroxyphenyl).
- Representative compounds of the invention are:
- the compounds of formula I of the present invention can be prepared by a method starting with the known steroid ester of the formula:
- the dehydrogenation step includes the stages of (1) dehydrogenating said starting material to produce the corresponding compound containing a double bond in the 1,2-position of the A-ring, (2) converting the 17-carbomethoxy substituent into a 17 ß-acyl substituent and, if desired (3) alkylating the A-ring nitrogen to introduce 4-methyl or 4-ethyl substituents into the A-ring.
- the 4-aza nitrogen be unsubstituted.
- the dehydrogenation step can be carried out, e.g. according to the procedure of Dolling, et al.
- Stage (2) may consist of one or more chemical steps and if desired may take place before stage (1) or following stage (1) or stage (3).
- reaction with a Grignard reagent R 2 MgX gives the ketone, 17ß-R 3 CO-, corresponding to the R 2 moiety associated with the Grignard reagent.
- X is a 2-pyridylthio substituent and R 2 is defined as hereinabove.
- R 2 is p-hydroxybiphenyl
- this can be derived by starting with an appropriate bromobiphenylylphenol, e.g. p-bromobiphenylphenol, protecting the phenolic -OH with a conventional blocking group, e.g. trioganosilyl, i.e. t-butyldimethylsilyl, carrying out the Grignard reaction and then deblocking the silyl group by the use of, e.g. refluxing aqueous tetrabutylammonium fluoride.
- a conventional blocking group e.g. trioganosilyl, i.e. t-butyldimethylsilyl
- protected hydroxy is meanLthe alcoholic or carboxylic -OH groups which can be
- triorganosilyl groups e.g. t-butyldimethylsilyl, phenyldimethylsilyl, diphenylmethylsilyl, and the like.
- linear or branched alkyl including methyl, ethyl, propyl, isopropyl, n-butyl, isobutyl, sec-butyl and t-butyl.
- R- ⁇ MgX or R 2 -Li compound containing an thiophenyl substituted R 2 , e.g. p-methylthiophenyl magnesium chloride the corresponding 17ß-(substituted thio-benzoyl)-4-alkyl-4-aza-5 ⁇ -androst-1-en-3-one is prepared wherein phenyl is R 2 .
- R 2 MgX for all the species included within the scope of this invention, are available or can readily be made by one skilled in the art.
- R 2 is C 1 -C 4 alkyl thiophenyl
- R 2 can be formed from the appropriate C 1 -C 4 alkyl thiobromobenzene, e.g. p-methylthiobromobenzene.
- the formed C 1 -C 4 alkyl thiobenzene can be used to further prepare C 1 -C 4 alkyl sulfoxides by oxidation with e.g. m- chloroperbenzoic acid.
- the resulting sulfoxide can be further oxidized by the use of the m-chloroperbenzoic acid reaction to proceed for a longer period of time to form the C 1 -C 4 alkyl sulfone.
- the sulfoxide can be used in the Pummerer rearrangement to form the corresponding thiol.
- the -SO 2 N(C 1 -C 4 alkyl) 2 substituted phenyl (R 2 ) is formed from the appropriate bromobenzene, e.g. p-N,N-dimethylaminosulfobromobenzene which is used directly in the Grignard reaction to form the final product.
- thioalkyl groups on the phenyl ring i.e. -(CH 2 ) m SH, where m is 1-4, are readily formed via a four step procedure from an alkoxy alkyl phenyl bromide, Br-C 6 H 4 -
- said Grignard reagent contains a phenolic type R 2 moiety
- R 2 is hydroxyphenyl
- this can be derived by starting with an appropriate bromophenol, e.g. p-bromophenol, protecting the phenolic -OH with a conventional blocking group, e.g. trioganosilyl, i.e. t-butyldimethylsilyl, carrying out the Grignard reaction and then deblocking the silyl group by the use of, e.g. refluxing aqueous tetrabutylammonium fluoride.
- a conventional blocking group e.g. trioganosilyl, i.e. t-butyldimethylsilyl
- hydroxyalkyl bromophenol e.g. p-hydroxymethyl-bromobenzene, or p-hydroxyethylbromobenzene.
- R 2 is carboxyphenyl
- this can be obtained by the chromic acid oxidation of the appropriate hydroxymethylbenzene, e.g. p-bromo-hydroxymethylbenzene, formed as described above.
- R 2 is -O-C 1 -C 4 alkyl
- the appropriate bromo-O-C 1 -C 4 alkyl benzene e.g. p-methoxybromobenzene, is utilized for the Grignard reaction.
- protected hydroxy is meant the alcoholic or carboxylic -OH groups which can be
- triorganosilyl groups e.g. t-butyl-dimethylsilyl, phenyldunethylsilyl, diphenylmethylsilyl, and the like.
- ketone reduction products of I in combination with minoxidil for treatment of patterned alopecia, being secondary alcohols of the formula:
- R is selected from hydrogen, methyl and ethyl
- R 2 is (a) a monovalent radical selected from straight or branched
- heterocyclic radical selected from 2- or 4-pyridyl, 2- pyrrolyl, 2-fi ⁇ ryI or thiophenyl;
- R', R" and R'" are hydrogen or methyl, wherein the dotted line represents a double bond which can be present, and
- R 2 phenyl contains a carbonyl function, it can be selectively blocked and then regenerated after the borohydride
- the borohydride reduction can be carried out in, e.g.
- Another preferred embodiment of the invention is where;
- Z is -XR 4 , or -(CHR 1 ) n -XR 4 ;
- n 1-10;
- X is -O- or -S(O) p -
- R 1 can be the same or different when n is greater than 1 and is -H, aryl, or -C 1 -3 alkyl unsubstituted or substituted with aryl;
- R is -H, methyl or ethyl
- R 4 is 1) -C 1 -20 alkyl, unsubstituted or substituted with one or more of:
- aryl unsubstituted or substituted with one or more of aryl, R 7 or R 9 ,
- R 7 or R 9 , k) -C 3-10 cycloalkyl such as cyclohexyI,norbornyl, or
- R 7 is 1) -OH
- R 9 is 1) -C 1 -8 alkyl, unsubstituted or substituted with one or more
- R 4 is -C 1 -20 alkyl, unsubstituted or
- Another preferred embodiment of this invention is represented by compounds of general structural formula VI wherein R 4 is -C 1 -20 alkyl substituted with -CONR 5 R 5 , -COOR 6 or
- R 4 is aryl unsubstituted or substituted with one or more of aryl, R 7 or R 9 ; heterocycle unsubstituted or substituted with one or more of R 7 orR 9 ; or -C 3-10 cycloalkyl unsubstituted or substituted with one or more of R 7 or R 9 ; and X, R 7 and R 9 are defined as in general structural formula I.
- R 4 is -C 1-20 alkyl unsubstituted or
- aryl unsubstituted or substituted with one or more of aryl, R 7 or R 9 , heterocycle unsubstituted or substituted with one or more of R 7 or R 9 , or -C 3-10 cycloalkyl unsubstituted or substituted with one or more of R 7 or R 9 ,
- R 1 , n, p, R 5 , R 7 and R 9 are defined as in general structural formula I.
- Another preferred embodiment of this invention is represented by compounds of general structural formula VH wherein R 4 is -C 1-20 alkyl substituted with -CONR 5 R 5 , -COOR 6 or -CONR 8 CONHR 8 ,
- R 1 , n, R 5 , R 6 and R 8 are defined as in general structural formula I.
- Another preferred embodiment of this invention is represented by compounds of formula VII wherein R 4 is aryl unsubstituted or substituted with one or more of aryl, R 7 or R 9 ;
- R 7 or R 9 heterocycle unsubstituted or substituted with one or more of R 7 or R 9 ; or -C 3-10 cycloalkyl unsubstituted or substituted with one or more of R 7 or R 9 ; and X, R 1 , n, R 7 and R 9 are defined as in general structural formula I.
- Novel compounds of the present invention include but are not limited to the following compounds:
- Novel compounds of this invention further include, but are not limited to:
- a basic group i.e. amino
- acidic salts i.e. hydrochloride, hydrobromide, acetate, pamoate, and the like
- a basic group i.e. amino
- acidic salts i.e. hydrochloride, hydrobromide, acetate, pamoate, and the like
- esters can be employed, e.g. acetate, maleate, pivaloyloxymethyl, and the like, and those esters known in the art for modifying solubility or hydrolysis characteristics for use as sustained release or prodrag formulations.
- the compounds of the present invention may have asymmetric centers and occur as racemates, racemic mixtures and as individual diastereomers, with all isomeric forms being included in the present invention.
- variable e.g., aryl, heterocycle, R 1 , R 2 , n, X, etc.
- any variable e.g., aryl, heterocycle, R 1 , R 2 , n, X, etc.
- alkyl is intended to include both branched- and straight-chain saturated aliphatic hydrocarbon groups having the specified number of carbon atoms (Me is methyl, Et is ethyl, Pr is propyl, Bu is butyl); "alkoxy” represents an alkyl group of indicated number of carbon atoms attached through an oxygen bridge.
- Cycloalkyl is intended to include saturated mono-, bi- and tricyclic ring groups, such as cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl (Cyh), cycloheptyl, norbomanyl and adamantyl.
- Alkenyl is intended to include hydrocarbon groups of either a straight or branched configuration with one or more carbon-carbon double bonds which may occur in any stable point along the chain, such as ethenyl, propenyl, butenyl, pentenyl, and the like.
- Hydrocarbon as used herein, means fluoro, chloro, bromo and iodo.
- aryl is intended to mean phenyl (Ph) or naphthyl.
- heterocycle or heterocyclic as used herein except where noted, represents a stable 5- to 7-membered
- unsaturated and which consists of carbon atoms and from one to three heteroatoms selected from the group consisting of N, O and S, and wherein the nitrogen and sulfur heteroatoms may optionally be oxidized, and the nitrogen heteroatom may optionally be
- heterocyclic ring may be attached at any heteroatom or carbon atom which results in the creation of a stable structure.
- heterocyclic elements include piperidinyl, piperazinyl, 2-oxopiperazinyl, 2-oxopiperidinyl, 2-oxopyrrolodinyl, 2-oxoazepinyl, azepinyl, pyrrolyl, 4-piperidonyl, pyrrolidinyl, pyrazolyl,
- pyrazolidinyl imidazolyl, imidazolinyl, imidazolidinyl, pyridyl, pyrazinyl, pyrimidinyl, pyridazinyl, oxazolyl, oxazolidinyl, isoxazolyl, isoxazolidinyl, morpholinyl, thiazolyl, thiazolidinyl, isothiazolyl, quinuclidinyl, isothiazolidinyl, indolyl, quinolinyl, isoquinolinyl, benzimidazolyl, thiadiazoyl, benzopyranyl, benzothiazolyl, benzoxazolyl, furyl, tetrahydrofuryl,
- thiamorpholinyl sulfoxide thiamo ⁇ holinyl sulfone, and oxadiazolyl.
- Morpholino is the same as morpholinyl.
- Preferred heterocycles are piperidinyl, 2-oxopyrroIodinyl, pyrrolyl, pyrazolyl, imidazolyl, pyridyl, pyrazinyl, pyrimidinyl, pyridazinyl, oxazolyl, isoxazolyl, mo ⁇ holinyl, thiazolyl, isothiazolyl, quinuclidinyl, indolyl,
- quinolinyl isoquinolinyl, benzimidazolyl, thiadiazoyl,
- benzothiazolyl benzoxazolyl, furyl, tetrahydrofuryl, thienyl, and benzothienyl.
- heteroaryl represents a stable 5- to 7-membered monocyclic unsaturated heterocyclic ring, which consists of carbon atoms and from one to three heteroatoms selected from the group consisting of N, O and S, and wherein the nitrogen and sulfur heteroatoms may optionally be oxidized, and the nitrogen heteroatom may optionally be quatemized.
- the compounds of this invention can be made from a steroid alcohol starting material, represented by general structural formula VIII:
- R 2 is hydrogen, or a is a double bond, b is a single bond and R 2 is hydrogen, or a is a single bond, b is a double bond and R 2 is absent;
- R 3 is -H, methyl or ethyl;
- Y is -OH or -(CHR 1 ) n -OH;
- R 1 is -H, aryl, or C 1-3 alkyl
- 4-azasteroid-20-alcohols of formula VIII may be made by several methods well known to those skilled in the art.
- 4-azasteroids containing a 17-carbonyl group e.g. carboxaldehyde
- the appropriate organo-metallic reagent e.g. carboxaldehyde
- an appropriate 17-ketone may be reduced (e.g. with sodium
- ketones may be made by several methods well known in the art; one particularly useful method is that of A. Bhattacharya et al., Synthetic Communications 20 (17), 2683-2690 (1990), in which an activated carbonyl compound is reacted with a suitable Grignard reagent to give the desired ketone.
- Other activated carbonyl compounds e.g. pyridine thioesters
- These alcohol functions may be constructed both before and after the formation of the 4-aza moiety.
- (iv) can generally be made by forming the mesylate (iii) of alcohol
- M + S--R 4 is a metal ion, e.g. Na + or K + , and R 4 is as defined in formula I.
- M + S--R 4 reagents are either commercially available, such as sodium thioethoxide or potassium thiophenoxide, or can be generated by methods well known in the art, e.g., as described in J. Org. Chem. 40, p 1181 (1975) or J. Chem. Soc. p 3127 (1928). FLOWSHEET IV
- the starting alcohol (v) can be treated with a diazo-reagent (vi) using techniques well known in the art, e.g. using boron trifluoride etherate or
- Diazo-reagents such as diazomethane, diphenyldiazomethane, benzyldiazo-acetate, etc.
- Diazo-reagents are generated by methods well know in the art, such as by the methods described in the following publications: British Patent 1,533,381; British Patent 1,459,285; J. Chem. Soc. Perkins I, p. 2030 (1975); Organic Synthesis. Collective Vol. III, p. 351 (1955); J. Org. Chem., 24, p. 560 (1959).
- R a is -H and R b is -COOC 2 H 5 in compound (vii)
- hydrolysis of the ester with base followed by treatment with acid produces compound (viii).
- the acid (viii) can be coupled with an amine, e.g. an arylamine such as aniline, 4-t-butyl aniline, or p-amino-acetophenone, by common amide coupling procedures well known in the art, e.g., using the carbodiimide method with reagents such as DCC or DIC in the presence of DMAP, to form an amide exemplified by (x).
- the 5 ⁇ -4-azandrostan-3-on-17-yloxyacetic acid and ethyl 5 ⁇ -4-azaandrostan-3-on-17ß-yloxy-acetate analogs can be prepared according to general scheme 2 but are more preferably prepared according to the routes described in Examples 17 and 21 herein.
- Amide compounds of formula (x) can also be made by alternative methods well known in the art, e.g., by reacting (vii) wherein R a is -H and R b is -COOC 2 H 5 directly with an unsubstituted or substituted aryl-NH 2 compound and heating the reaction, e.g., to about 170°C - 180°C.
- Another method e.g., is to form a mixed anhydride of acid (viii) and react it with the desired primary amine to obtain compounds of formula (x).
- the starting alcohol (v) can be treated with a strong base, such as NaH or KOH, in an appropriate solvent such as DMF or DMSO, followed by treatment with an alkyl- or alkenyl-halide (xii-a), such as hexyliodide or allylbromide for example, to form the corresponding alkyl- or alkenyl-ether product (xiii-a).
- a strong base such as NaH or KOH
- an appropriate solvent such as DMF or DMSO
- an alkyl- or alkenyl-halide such as hexyliodide or allylbromide for example
- aryl ether and heteroaryl ether products can be prepared by treating the steroid alcohol starting material with a fluoroaryl or
- fluoroheteroaryl compound (xii-b) such as p-nitrofluorobenzene, p-cyanofluoro-benzene or 3-fluoropyridine for example, and NaH or KOH in an appropriate solvent such as DMF or DMSO, with
- KOH/DMF and KOH/DMSO being preferred.
- aryl ether and heteroaryl ether products of formula (xiii-b) can be prepared by treating the steroid alcohol starting material with an unsubstituted or substituted hydroxy aryl or hydroxy heteroaryl compound such as phenol or 4-hydroxybiphenyl for example, and triphenylphosphine and diethyl azodicarboxylate (DEAD).
- the ether product will have stereochemistry at the 17-position that is the opposite of the starting alcohol when Y is -OH in formula (i).
- 4-methyl-17 ⁇ -phenoxy-5 ⁇ -4-azaandrostan-3-one is the product of 17ß- hydroxy-4-methyl-5 ⁇ -4-azaandrostan-3-one and phenol.
- Heteroaryl ether products can be reduced by methods well known in the art, e.g., by hydrogenation in an appropriate solvent such as MeOH, in the presence of a catalyst such as palladium or platinum on carbon, to obtain compounds of formula I wherein R 4 is a saturated heterocycle.
- compounds of formula (xvii) can be prepared by treating the amino hydrochloride derivative (xv) with the appropriate anhydride reagent using methods well known to those skilled in the art.
- "R” in Scheme 4 can be heterocycle, "A” as defined in the generic description of compounds of formula I, or -(CH 2 ) q -CO-Q, wherein the variables
- R d is -(CH 2 ) q -CO-Q
- the cyano group of compound (xiv), wherein R c is -CN can be hydrolyzed by methods well known in the art, e.g., by treatment with H 2 O 2 and base such as
- the primary amide of (xvi) can be alkylated by methods well known in the art, such as with methyl iodide, for example, to make the secondary or tertiary amide derivatives.
- the diazonium salt of compound (xv) can be made by treatment of (xv) with HNO 2 or an alkyl nitrite.
- the resulting diazonium salt can be used as an intermediate in a variety of reactions to replace the diazonium moiety to make other substituted aryl ether derivatives.
- the diazonium salt moiety can be replaced with a halo, -CN, -OH or alkoxy group by common methods well known to those skilled in the art.
- the diazonium moeity can be replaced with hydrogen to yield the unsubstituted aryl ether derivative.
- the ethers of this invention may be
- a 20-alkoxy-substituted pregn-4-en-3-one may be oxidized with permanganate periodate to the corresponding seco-acid which is then reacted with an appropriate amine to give, after reduction of the first obtained 4-aza-5-enesteroid, the desired 20-ether-substituted-5 ⁇ -4-azapregnan-3-one.
- R 4 is -C 1-20 alkyl, unsubstituted or substituted with one or more of
- R 7 , and R 9 are all as defined in formula I.
- Another preferred embodiment of this invention is represented by compounds of general structural formula IX wherein R 4 is -C 1 -20 alkyl substituted with -CONR 5 R 5 , -COOR 6 or
- R 5 , R 6 , and R 8 are all as defined in formula I.
- R 5 , R 7 , and R 9 are all as defined in formula I.
- R 4 is -C 1 -20 alkyl, unsubstituted or substituted with one or more of
- Another preferred embodiment of this invention is represented by compounds of general structural formula X wherein R 4 is -C 1 -20 alkyl substituted with -CONR 5 R 5 , -COOR 6 or
- Another preferred embodiment of this invention is represented by compounds of formula X wherein R 4 is aryl
- R 9 heterocycle unsubstituted or substituted with one or more of R 7 or R 9 ; -C 3-10 cycloalkyl unsubstituted or substituted with one or more of R 7 or R 9 ; -NR 5 R 5 ; or -OR 5 ;
- Novel compounds of the present invention include but are not limited to the following compounds:
- Novel compounds of the present invention further include, but are not limited to the following compounds:
- compositions of formula I where a basic or acidic group is present in a compound of formula I, such as on the substituted alkyl, cycloalkyl, aryl or heterocyclic moiety.
- an acidic substituent i.e. -COOH
- ammonium, sodium, potassium, calcium salt, and the like for use as the dosage form.
- a basic group i.e. amino
- acidic salts i.e. hydrochloride, hydrobromide, acetate, pamoate, and the like
- a basic group i.e. amino
- acidic salts i.e. hydrochloride, hydrobromide, acetate, pamoate, and the like
- esters can be employed, e.g. acetate, maleate, pivaloyloxymethyl, and the like, and those esters known in the art for modifying solubility or hydrolysis characteristics for use as sustained release or prodrug formulations.
- the compounds of the present invention may have asymmetric centers and occur as racemates, racemic mixtures and as individual diastereomers, with all isomeric forms being included in the present invention.
- the compounds of this invention can alternatively be made generally from a steroid alcohol starting material, represented by formula XI: wherein a and b are both single bonds and R 2 is hydrogen, or
- a is a double bond, b is a single bond and R 2 is hydrogen, or a is a single bond, b is a double bond and R 2 is absent;
- R 1 is -H, aryl, or C 1-3 alkyl unsubstituted or substituted with aryl;
- R 3 is -H, methyl or ethyl; and n is zero through 10.
- 4-azasteroid-20-aIcohols of Formula XI may be made by several methods well known to those skilled in the art.
- 4-azasteroids containing a 17-carbonyl group e.g. carboxaldehyde
- theappropriate organo-metallic reagent e.g. carboxaldehyde
- an appropriate 17-ketone may be reduced (e.g. with sodium
- ketones may be made by several methods well known in the art; one particularly useful method is that of A. Bhattacharya et al., Synthetic Communications 20(17), 2683-2690 (1990), in which an activated carbonyl compound is reacted with a suitable Grignard reagent to give the desired ketone.
- Other activated carbonyl compounds e.g. pyridine thioesters
- These alcohol functions may be constructed both before and after the formation of the 4-aza moiety.
- One method of preparing compounds of formula I is to condense the starting steroid alcohol with an acid of formula (ii)
- R 4 -COOH (ii) under conditions known to those skilled in the art, e.g., in an appropriate solvent such as CH 2 CI 2 , in the presence of 4- (dimethylamino)-pyridine (DMAP) and N,N -dicyclohexylcarbodiimide (DCC).
- DMAP dimethylamino-pyridine
- DCC N,N -dicyclohexylcarbodiimide
- Another method of preparing compounds of formula I is to combine the starting alcohol (i) with an acid chloride of formula (iii) or acid anhydride or mixed anhydride of formula (iv)
- Carbamate derivatives of formula I can be prepared by reacting the starting alcohol XI with an isocyanate compound, such as benzyl isocyanate or t-butylisocyanate for example, under conditions known to those skilled in the art, e.g., under dry conditions in an appropriate solvent such as benzene, in the presence of a base such as 1,8-diazabicyclo[5.4.0]undec-7-ene (DBU), with heating e.g. to 60°-70°C.
- an isocyanate compound such as benzyl isocyanate or t-butylisocyanate for example, under conditions known to those skilled in the art, e.g., under dry conditions in an appropriate solvent such as benzene, in the presence of a base such as 1,8-diazabicyclo[5.4.0]undec-7-ene (DBU), with heating e.g. to 60°-70°C.
- DBU 1,8-diazabicyclo[
- the thiol esters may be conveniently prepared from the corresponding alcohol via the literature procedure described in Tetrahedron Letters, 22 (1981) pp. 3119-3122, that is, the alcohol and a thiolacid are reacted together in the presence of the preformed adduct from triphenylphosphine and diisopropyl azodicarboxylate.
- the free thiol obtained from these thiolesters via standard saponification or reduction methods may then be acylated via standard procedures to obtain other thiolesters.
- A is:
- R 3 can not be C 1-12 alkyl.
- R 1 is:
- R 2 is:
- C 1-20 alkyl ' R 3 is:
- R 5 is:
- W is , or ;
- x is an integer from 1 to 25;
- A is:
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US08/341,602 US5710275A (en) | 1992-05-20 | 1993-05-14 | 7β-substituted-4-aza-5α-androstan-3-ones as 5α-reductase inhibitors |
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- 1993-05-14 WO PCT/US1993/004643 patent/WO1993023420A1/en active Application Filing
- 1993-05-17 IL IL105715A patent/IL105715A/xx not_active IP Right Cessation
- 1993-05-19 DE DE69333317T patent/DE69333317T2/de not_active Expired - Fee Related
- 1993-05-19 CA CA002096616A patent/CA2096616A1/en not_active Abandoned
- 1993-05-19 ES ES96202933T patent/ES2210336T3/es not_active Expired - Lifetime
- 1993-05-19 MX MX9302932A patent/MX9302932A/es not_active IP Right Cessation
- 1993-05-19 AT AT93303882T patent/ATE156838T1/de not_active IP Right Cessation
- 1993-05-19 AT AT96202933T patent/ATE255125T1/de not_active IP Right Cessation
- 1993-05-19 ES ES93303882T patent/ES2106965T3/es not_active Expired - Lifetime
- 1993-05-19 EP EP96202933A patent/EP0778284B1/en not_active Expired - Lifetime
- 1993-05-19 ZA ZA933497A patent/ZA933497B/xx unknown
- 1993-05-19 DK DK93303882.0T patent/DK0572166T3/da active
- 1993-05-19 CN CN93107704A patent/CN1087092A/zh active Pending
- 1993-05-19 EP EP93303882A patent/EP0572166B1/en not_active Expired - Lifetime
- 1993-05-19 DE DE69313018T patent/DE69313018T2/de not_active Expired - Fee Related
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Cited By (19)
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US5510485A (en) * | 1992-05-20 | 1996-04-23 | Merck & Co., Inc. | 17-ester, amide, and ketone derivatives of 3-oxo-4-azasteroids as 5A-reductase inhibitors |
US5710275A (en) * | 1992-05-20 | 1998-01-20 | Merck & Co., Inc. | 7β-substituted-4-aza-5α-androstan-3-ones as 5α-reductase inhibitors |
US5693809A (en) * | 1992-05-20 | 1997-12-02 | Merck & Co., Inc. | Substituted 4-aza-5α-androstan-ones as 5α-reductase inhibitors |
US5578726A (en) * | 1992-05-20 | 1996-11-26 | Merck & Co., Inc. | Process for producing 7 β-substituted-4-aza-5 α-androstan-3-ones |
US5693810A (en) * | 1992-10-06 | 1997-12-02 | Merck & Co., Inc. | 17 β-carboxanilides of 4-aza-5α-androstan-3-ones as 5α-reductase inhibitors |
US5438061A (en) * | 1993-07-16 | 1995-08-01 | Merck & Co., Inc. | 7-substituted-δ4-6-azasteroid derivatives as 5α-reductase inhibitors |
US5565467A (en) * | 1993-09-17 | 1996-10-15 | Glaxo Wellcome Inc. | Androstenone derivative |
US5846976A (en) * | 1993-09-17 | 1998-12-08 | Glaxo Wellcome Inc. | Androstenone derivative |
US5977126A (en) * | 1993-09-17 | 1999-11-02 | Glaxo Wellcome Inc. | Androstenones |
MY119778A (en) * | 1993-09-17 | 2005-07-29 | Glaxo Inc | Androstenone derivative. |
WO1995012398A1 (en) * | 1993-11-04 | 1995-05-11 | Merck & Co., Inc. | 7-substituted-4-aza-steroid derivatives as 5-alpha- reductase inhibitors |
US5696266A (en) * | 1994-09-07 | 1997-12-09 | Merck & Co., Inc. | Process for the stereoselective reduction of steroid enelactams |
US5817802A (en) * | 1994-09-07 | 1998-10-06 | Merck & Co., Inc. | Process for the stereoselective reduction of steroid enelactams |
US5817818A (en) * | 1994-09-16 | 1998-10-06 | Glaxo Wellcome Inc. | Androstenones |
US5541322A (en) * | 1994-10-14 | 1996-07-30 | Glaxo Wellcome Inc. | Synthesis of 6-azaandrostenones |
US5656613A (en) * | 1995-01-04 | 1997-08-12 | Merck & Co., Inc. | Treatment of hyperandrogenic conditions |
US6365597B1 (en) | 1996-02-14 | 2002-04-02 | Aventis Pharmaceuticals Inc. | 4-aza steroids |
US5872126A (en) * | 1996-09-06 | 1999-02-16 | Merck & Co., Inc. | Methods and compositions for treating preterm labor |
US5998427A (en) * | 1998-05-14 | 1999-12-07 | Glaxo Wellcome Inc. | Androstenones |
Also Published As
Publication number | Publication date |
---|---|
ES2210336T3 (es) | 2004-07-01 |
IL105715A (en) | 1997-07-13 |
ZA933497B (en) | 1993-12-14 |
MX9302932A (es) | 1995-01-31 |
DE69313018T2 (de) | 1998-02-19 |
EP0778284A2 (en) | 1997-06-11 |
DK0572166T3 (da) | 1997-09-01 |
DE69333317T2 (de) | 2004-08-19 |
ATE156838T1 (de) | 1997-08-15 |
US5710275A (en) | 1998-01-20 |
DE69313018D1 (de) | 1997-09-18 |
ATE255125T1 (de) | 2003-12-15 |
JPH06100587A (ja) | 1994-04-12 |
EP0572166A1 (en) | 1993-12-01 |
EP0572166B1 (en) | 1997-08-13 |
ES2106965T3 (es) | 1997-11-16 |
GR3024884T3 (en) | 1998-01-30 |
EP0778284B1 (en) | 2003-11-26 |
IL105715A0 (en) | 1993-09-22 |
AU3869893A (en) | 1993-11-25 |
AU662224B2 (en) | 1995-08-24 |
CA2096616A1 (en) | 1993-11-21 |
CN1087092A (zh) | 1994-05-25 |
EP0778284A3 (en) | 1997-08-13 |
DE69333317D1 (de) | 2004-01-08 |
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